Plain language summary
Anhedonia is a common feature of depression, where a person lacks
general interest, motivation, and enjoyment. It is thought that a lack
of dopamine is associated with symptoms of anhedonia in people with
depression. Some studies found that pro-dopaminergic drugs, which are
drugs that can mimic the effects of dopamine in the brain, can reduce
symptoms of anhedonia. However, it is unknown how these drug treatments
can target the processes in our body that cause anhedonia.
The goal of this project was to review information from published
studies on how pro-dopaminergic drugs (medications such as certain
antidepressants or stimulants) target processes in the body that cause
anhedonia. As this is a living systematic review, the team will search
for new studies every 3 months and this report will be updated when new
evidence is available.
We found that pro-dopaminergic drugs reduced anhedonia and decreased
anxiety in human studies. These studies also mentioned that the dopamine
agents were tolerated well, however, many participants discontinued the
treatment due to side effects. Similarly, we found that pro-dopaminergic
agents increased dopamine levels in animals.
Further research is needed to better understand the role of
pro-dopaminergic agents in reducing anhedonia, specifically on reward
and reinforcement tasks which will help us examine the mechanism
underlying anhedonia in more detail. Future work should explore how the
different mechanisms of these drugs affect symptoms of anhedonia, as
well as adding other drugs to a patient’s treatment in addition to the
pro-dopamine agent. Future studies should also include a range of
pro-dopaminergic drugs as currently the majority of studies measuring
anhedonia used one antidepressant. This would allow us to be more
confident in the effects of dopamine rather than the one
antidepressant.
1. Methods (brief)
In this first iteration of the living systematic review we searched
for randomised controlled trials that compared pro-dopaminergic
interventions to placebo in adults with unipolar depression
(i.e. above-threshold symptoms on any standardised measure, or a
clinical diagnosis based on any operationalised criteria).
Eight databases were searched from inception up to the 9th of
November, 2023 (see protocol
for full search strings). Database search results were imported into EPPI-Reviewer and duplicates were removed
prior to screening. All steps related to record screening and data
extraction were completed in EPPI-Reviewer.
Titles and abstracts of the identified records were screened by at
least two reviewers (CF, MC, JK, JP). We retrieved the full-texts and
any supporting documents for all records that were not excluded at the
title and abstract screening stage. The full-text screening was
conducted by at least two reviewers (CF, JK, JP, AK, EB). Conflicts at
title and abstract, and full-text screening, were resolved through
discussion between the two reviewers and involvement of a third reviewer
(AC, EGO).
We focused on the following outcomes: - anhedonia symptom severity:
using anhedonia-specific scales, anhedonia-specific sub-scales, or
individual items focusing on anhedonia (observer-rated or self-rated).
Continuous, primary outcome. - anxiety symptom severity: as per observer
or self-reported standardised scales. Continuous, secondary outcome. -
acceptability: proportion of participants dropping out for any reason.
Binary, secondary outcome. - tolerability: the proportion of
participants dropping out due to an adverse event. Binary, secondary
outcome. - safety: the proportion of participants reporting specific
adverse events (nausea, headache, insomnia, constipation, dizziness, dry
mouth, vomiting). Binary, secondary outcome.
Additional information on the full study eligibility criteria can be
found in the pre-published protocol.
For anhedonia and anxiety symptom severity, we extracted outcome data
reported at 8 weeks post-treatment or manipulation. If the information
at 8 weeks was not available, we considered eligible data ranging
between 4 and 12 weeks (with preference to the time point closest to 8
weeks and, if equidistant, the longer outcome). For acceptability,
tolerability, safety and safety (specific adverse events), we extracted
outcome data reported at the end of the studies.
When extracting continuous outcomes we extracted mean and standard
deviation to two decimal places. Where standard error was reported, we
converted the value to standard deviation. Baseline and endpoint values
were extracted. These were preferred to change in score and endpoint, in
which case the missing value was calculated by adding or subtracting the
change in score from the time point given.
When extracting dichotomous outcomes we extracted natural numbers and
where only percentages of participant groups were reported, a value was
calculated and rounded up to the nearest natural number. Adverse events
were extracted using the exact wording used to report them in the
included studies.
Relevant data was extracted using EPPI-Reviewer by at least two reviewers (CF,
CA, EB, JK). EPPI-Reviewer was used to screen records, extract data, and
assess risk of bias.
We assessed risk of bias with the RoB2 tool (Higgins et al. 2019).
All outcomes for all included studies were assessed by at least two
reviewers (JK, CF, CA, AH) and conflicts were resolved by discussion
between reviewers. To evaluate biases due to missing evidence, the
ROB-ME tool (Page et al. 2023) was used with the same double screening
and conflict resolution process as described above.
Effect sizes were calculated as standardised mean differences (SMDs)
for continuous outcomes (anhedonia and anxiety symptom severity) and
odds ratios (ORs) for dichotomous outcomes (acceptability, tolerability,
and specific-adverse events). We calculated the 95% confidence interval
(CI) around the pooled effect size for each meta-analysis.
Meta-analyses were conducted using a random effects model with the
inverse variance method, using the restricted maximum-likelihood
estimator for 𝞽2 and the Hartung-Knapp correction method to
adjust 95% confidence intervals, if there are at least five studies.
Prediction intervals of the overall pooled effect were calculated to
convey the amount of heterogeneity.
In order to better contextualise pro-dopaminergic interventions
within wider literature on the effects of antidepressants on anhedonia,
we aggregated individual participant data (IPD) on the MADRS “inability
to feel” item from 34 randomised controlled trials (14054 participants)
on antidepressants in people with depression that we had access to. We
utilised this post-hoc analysis to add further evidence on the impact of
non-dopaminergic intervantions on anhedonia in depression and in doing
so, better understand the evidence we analysed on dopamine-specific
drugs. We performed the following analyses to estimate the performance
of bupropion versus placebo at the primary outcome (i.e. reduction in
anhedonia scores):
- aggregated IPD, all antidepressants and placebo, random effects
network meta-analysis.
- aggregated IPD, bupropion versus placebo, random effects pairwise
meta-analysis.
- combination of aggregated IPD and early studies identified in this
living systematic review for which IPD were not available, random
effects pairwise meta-analysis.
Meta-regressions were planned for the following variables: mean age
of participants, mean anhedonia baseline score, mean anxiety baseline
score, sex (proportion of female participants), and planned treatment
duration. Meta-regressions were only conducted for outcomes where data
was available from 10 or more studies.
Summary of evidence tables were constructed for all outcomes
including a summary of the meta-analytic result, biases within-study,
across-study, and due to indirectness.
Please refer to the protocol
and the extended data for more details.
A list of abbreviations can be found towards the end of the
document.
